Sai Ram Keithi-Reddy

Stroke in Patients With Type 2 Diabetes Mellitus, Chronic Kidney Disease, and Anemia Treated With Darbepoetin Alfa The Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) Experience

Background— More strokes were observed in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) among patients assigned to darbepoetin alfa. We sought to identify baseline characteristics and postrandomization factors that might explain this association. Methods and Results— A multivariate logistic regression model was used to identify baseline predictors of stroke in 4038 patients with diabetes mellitus, chronic kidney disease, and anemia randomized to receive darbepoetin alfa or placebo. To determine whether postrandomization blood pressure, hemoglobin level, platelet count, or treatment dose were responsible for the increased risk related to darbepoetin alfa, we performed a nested case-control analysis (1:10 matching) identifying nonstroke controls with propensity matching. The risk of stroke was doubled with darbepoetin alfa. Overall, 154 patients had a stroke, 101/2012 (5.0%) in the darbepoetin alfa arm and 53/2026 (2.6%) in the placebo arm (hazard ratio 1.9; 95% confidence interval, 1.4–2.7). Independent predictors of stroke included assignment to darbepoetin alfa (odds ratio 2.1; 95% confidence interval, 1.5–2.9), history of stroke (odds ratio 2.0; 95% confidence interval, 1.4–2.9), more proteinuria, and known cardiovascular disease. In patients assigned to darbepoetin alfa, postrandomization systolic and diastolic blood pressure, hemoglobin level, platelet count, and darbepoetin alfa dose did not differ between those with and without stroke. Additional sensitivity analyses using maximal values, latest values, or changes over varying periods of exposure yielded similar results. Conclusions— The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa–related stroke. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00093015.

Stroke in Patients With Type 2 Diabetes Mellitus, Chronic Kidney Disease, and Anemia Treated With Darbepoetin Alfa

Background— More strokes were observed in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) among patients assigned to darbepoetin alfa. We sought to identify baseline characteristics and postrandomization factors that might explain this association. Methods and Results— A multivariate logistic regression model was used to identify baseline predictors of stroke in 4038 patients with diabetes mellitus, chronic kidney disease, and anemia randomized to receive darbepoetin alfa or placebo. To determine whether postrandomization blood pressure, hemoglobin level, platelet count, or treatment dose were responsible for the increased risk related to darbepoetin alfa, we performed a nested case-control analysis (1:10 matching) identifying nonstroke controls with propensity matching. The risk of stroke was doubled with darbepoetin alfa. Overall, 154 patients had a stroke, 101/2012 (5.0%) in the darbepoetin alfa arm and 53/2026 (2.6%) in the placebo arm (hazard ratio 1.9; 95% confidence interval, 1.4–2.7). Independent predictors of stroke included assignment to darbepoetin alfa (odds ratio 2.1; 95% confidence interval, 1.5–2.9), history of stroke (odds ratio 2.0; 95% confidence interval, 1.4–2.9), more proteinuria, and known cardiovascular disease. In patients assigned to darbepoetin alfa, postrandomization systolic and diastolic blood pressure, hemoglobin level, platelet count, and darbepoetin alfa dose did not differ between those with and without stroke. Additional sensitivity analyses using maximal values, latest values, or changes over varying periods of exposure yielded similar results. Conclusions— The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa–related stroke. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00093015.

Association of anemia and erythropoiesis stimulating agents with inflammatory biomarkers in chronic kidney disease

Inflammatory cytokines are important predictors of cardiovascular mortality especially in patients with chronic kidney disease. Here we explored the relationship of anemia and epoetin treatment to inflammatory cytokine levels in patients with chronic kidney disease. One hundred non-dialysis patients with chronic kidney disease over 18 years of age were evenly split into anemic and non-anemic cohorts. Of the 50 anemic patients, 23 were receiving erythropoiesis stimulating agents treatments. Levels of tumor necrosis factor (TNF)-alpha were found to be significantly higher and serum albumin was significantly lower with trends towards higher interleukin (IL)-6 and IL-8 in anemic compared to non-anemic patients. Further analysis by multiple logistic regression found that anemic patients treated with erythropoiesis stimulating agents had significantly higher odds for the upper two quartiles for IL-6, IL-8 and TNF-alpha compared to non-anemic patients. Our study found that the anemia of chronic kidney disease was associated with up regulation of TNF-alpha, and possibly IL-6 and IL-8 along with increased levels of these proinflammatory cytokines in patients treated with epoetin.

Managing anemia in dialysis patients: hemoglobin cycling and overshoot

CASE PRESENTATION A 67-year-old African American female with end-stage renal disease secondary to renal artery stenosis and ischemic nephropathy presents with increased somnolence of 1-day duration. Past medical history is notable for depression, mild dementia, glaucoma, gastroesophageal reflux disease, Graves disease that is inactive, diastolic heart failure, atrial fibrillation, and peripheral vascular disease. Two years prior to admission, the patient had undergone a dobutamine stress test for the work-up of dyspnea that was reported normal. The patient had a left brachio-cephalic arteriovenous graft inserted in February 2004. In November 2006, 2 months before the present admission, the graft required a declotting procedure and angioplasty and stenting of two lesions in the cephalic vein. At the same time, large pseudoaneurysms of the mid-venous and mid-arterial limbs were also identified. Medications included aspirin, diltiazem, amiodarone, esomeprazole, salmeterol, sevelamer, paricalcitol, and metoprolol. The patient was receiving epoetin at each dialysis treatment using an anemia protocol (10 000 U every dialysis treatment, three times each week, that had been intensified over the prior 3 months; Figure 1). Approximately 1 month prior to admission, the patient had received iron gluconate 125 mg x 1 dose. Social history was significant for the patient living at home with a nephew as her principal caregiver. There was no significant family history. Review of systems was not possible as patient was too somnolent. On examination the patient was drowsy. Blood pressure was 120/70 mm Hg and heart rate was 61 beats per min. She was afebrile and had normal respiratory rate. Pupils bilaterally were equal and reactive to light. Other cranial nerves, motor, and sensory examination was grossly normal. The examination of other systems was otherwise unremarkable except for 1 + edema bilaterally and the absence of a thrill or bruit over the left brachiocephalic arteriovenous graft. Laboratory testing on admission revealed a serum sodium of 140mEq/l, potassium 5.6 mEq/l, chloride 90 mEq/l, bicarbonate 33mEq/l, blood urea nitrogen 30 mg/dl, creatinine 5.9 mg/dl, glucose 42 mg/dl. Calcium, phosphate, and liver function tests, including transaminases and bilirubin, were within normal limits, except for alkaline phosphatase of 120 lU and serum albumin, 3 mg/dl (normal range 3-5 mg/dl); hematocrit was 55.9%; hemoglobin (Hgb) 16.8 mg/dl, white blood cell count was 6.42 x 10 6 l -1 (normal range 4.5-11 x10 6 l -1 ), platelets 219000. Her laboratory records from 2 weeks previously, as checked in her outpatient dialysis unit, showed Hgb level of 13.1 mg/dl, transferrin saturation of 23%, serum ferritin level of 283 ng ml -1 , and serum albumin level of 3.1 g/dl.

Endothelial activation markers in anemic non-dialysis chronic kidney disease patients.

Background/Aims: Anemia in chronic kidney disease is an independent predictor of cardiovascular disease (CVD). We explored the relationship between anemia and markers of inflammation and endothelial activation in non-dialysis chronic kidney disease (ND-CKD) patients to understand this mechanism. Methods: Cross-sectional analysis was performed on 30 adult ND-CKD patients for markers of inflammation and endothelial activation using a multiplexed immunoassay. Data were analyzed according to the anemic status defined by the modified World Health Organization criteria. Results: Seventeen patients were classified as anemic. Baseline characteristics by anemic status were similar except that anemic patients were older (p = 0.006), had lower estimated glomerular filtration rate (eGFR; p = 0.01) and higher prevalence of CVD (p = 0.02). Compared to non-anemic patients, log-transformed values of fibrinogen (p = 0.012); von Willebrand factor (vWF, p = 0.008), vascular cell adhesion molecule-1 (VCAM-1, p = 0.025) and C-reactive protein (p = 0.043) were elevated in anemic patients. Serum ferritin (p = 0.93) and serum albumin (p = 0.06) were not different. Age and eGFR-adjusted logistic regression analysis showed that anemic patients had increased odds for a composite of higher median values of fibrinogen, vWF and VCAM-1 (p = 0.01, odds ratio 8.1, 95% CI 1.08–111.0). Conclusion: We report the association of anemia with elevated markers of endothelial activation in ND-CKD patients. Longitudinal studies are needed to confirm our findings.

Acute coronary syndrome in ESRD patients.

CASE PRESENTATION A 55-year-old male with end-stage renal disease (ESRD) secondary to diabetic nephropathy on hemodialysis for 2 years via a tunneled catheter line was admitted to the Brigham & Women’s Hospital with chest pain. The chest pain was localized to the midline, radiated to the left arm, and was present at rest with no diaphoresis. His cardiac enzymes were elevated (troponin-I of 11.46 ng/ml and creatinine kinase-MB of 30.7 ng/ml) and his electrocardiogram (EKG) showed nonspecific ST–T wave changes that were unchanged from previous EKG 6 months earlier. He had a history of coronary artery disease (CAD) status post coronary artery bypass graft (CABG) 10 months earlier, type 1 diabetes mellitus since the age of 6 years, and peripheral neuropathy, blindness secondary to proliferative retinopathy, gastroparesis, neurogenic bladder, peripheral vascular disease (above-knee amputation of right limb), hypertension, and hypercholesterolemia. He had a failed living-related renal transplant because of recurrent diabetic nephropathy and chronic allograft nephropathy after 15 years. He had no history of stroke. His medications included aspirin, metoprolol, simvastatin, gemfibrozil, insulin, calcium acetate, sevelamer, epoeitin alfa, methadone, and hydromorphone hydrochloride. There was no significant family history of cardiovascular or renal disease. On physical examination, he was alert and afebrile, with a blood pressure of 135/60 mmHg, heart rate of 70 beats per minute, respiratory rate of 14 breaths per minute, with an oxygen saturation of 100% on room air and jugular venous pressure of 7 cm. His tunneled catheter site on the right side of the neck was clean, with no tenderness or erythema. Cardiac examination revealed distant heart sounds with no murmurs. The rest of the examination was unremarkable. CLINICAL DIAGNOSIS A clinical diagnosis of acute coronary syndrome (ACS) (a non-ST-elevation myocardial infarction (MI)) was made.

Route of Epoetin Administration Influences Hemoglobin Variability in Hemodialysis Patients

Background: Compared to the intravenous route, subcutaneous administration of epoetin requires lower dose and will be an attractive option for cost containment when bundling for dialysis is implemented. Hemoglobin variability defined as fluctuation of hemoglobin over time has not been well studied with respect to the route of administration. Methods: 157 prevalent-hemodialysis subjects were analyzed from an open-label, randomized study that compared the intravenous to the subcutaneous route of epoetin with identical weight-based dosing algorithm. Hemoglobin variability was defined as the number of weeks hemoglobin is outside the target range of 10–11 g/dl. Sensitivity analysis was performed. Results: 78 subjects in the intravenous and 79 in the subcutaneous group entered the 24-week dose maintenance phase. Baseline covariates were similar in both groups except for the dose of epoetin (lower in subcutaneous) and dialysis vintage (longer in intravenous). Patients on subcutaneous epoetin were outside the target range more weeks (p = 0.04) and had higher standard deviation of hemoglobin (p = 0.01) compared to the intravenous group. Conclusions: The subcutaneous route of epoetin was associated with modestly higher hemoglobin variability, probably reflecting greater sensitivity of the subcutaneous route and/or identical epoetin-dosing algorithm employed in both the arms. This study could serve as an important guide when bundling for dialysis services is implemented as switching from intravenous to subcutaneous administration is likely to occur.

Cytomegalovirus disease with Guillain–Barré syndrome in a cadaver renal allograft recipient: cause or coincidence

Anecdotal reports of acute inflammatory demyelinating polyneuropathy (Guillain–Barré syndrome) with cytomegalovirus (CMV) suggested as the etiological agent have been described in transplant recipients with poor prognosis. We describe a 48-year-old man, a cadaveric renal allograft recipient on cyclosporine, mycophenolate mofetil and prednisolone, who developed febrile illness with unexplained anemia followed by progressive weakness of the upper and lower limbs. He was diagnosed as a case of Guillain–Barré syndrome (GBS). His CMV serology was positive by polymerase chain reaction (PCR). We treated him with both gancyclovir and intravenous immunoglobulins within a week of the onset of GBS and observed rapid recovery. Thus, search for CMV is warranted in transplant patients presenting with GBS, as early initiation of treatment with gancyclovir and immunoglobulins can help expedite recovery.

Diffuse vascular calcification in a dialysis patient.

CASE PRESENTATION A 35-year-old Hispanic male on hemodialysis for end-stage renal disease (ESRD) secondary to diabetic nephropathy was admitted with chest pain and shortness of breath. The chest pain was localized to the midline, without any radiation or diaphoresis and was present at rest. The patient was bed-bound due to bilateral below-knee amputations. He had recurrent episodes of chest pain and shortness of breath in the past 3 months for which he was hospitalized. During these admissions, his cardiac enzymes were within normal limits. A stress test performed recently was technically limited, but showed a small inferior defect with normal left ventricular function. He had a past history of type I diabetes mellitus since the age of 10. Subsequently, he developed peripheral neuropathy, blindness secondary to retinopathy, nephropathy with ESRD, and underwent below-knee amputation of left and right limbs for severe peripheral vascular disease 6 and 12 years before, respectively. He had no history of cerebrovascular accident. He also had a past history of hypertension and hypercholesterolemia. His medications included lisinopril, metoprolol, nifedipine, aspirin, clopidogrel, and insulin. He had a strong family history of diabetes, with his mother and brother being diabetes patients. On physical examination, he was lethargic, afebrile with a blood pressure of 170/86 mm Hg, heart rate of 70 beats per minute, respiratory rate of 14 breaths per minute with an oxygen saturation of 97% on 21 of supplemental oxygen, and jugular venous pressure of 14cm. Cardiac examination revealed audible S3 and S4. Respiratory examination revealed fine rales at the left lung base and decreased breath sounds at the right lung base. His tunneled catheter site on the right side of the neck was clean, with no tenderness or erythema. The remainder of the systemic examination was unremarkable.

Contents Vol. 110, 2008

p21 Takis Anagnostopoulos Symposium: Renal and Epithelial Physiology and Pathophysiology June 26–27, 2008, Hôpital Necker, Paris, France Guest Editors: Planelles, G.; Edelman, A. (Paris)